PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD), the most common form of dementia, is closely associated with osteoporosis, another age-associated bone disorder. It has been proposed that there is an interplay between skeletal and central nervous system independent of age. However, the mechanistic link for the bone-brain interaction has been largely overlooked and understudied. We recently found that old mice, relative to young mice, have reduced blood vessel density and compromised blood-brain barrier (BBB) integrity in hippocampus, and our preliminary data suggests that bone/bone marrow cells secreted cytokines/growth factors, which may contribute to these age-associated brain vascular changes. Particularly, we detected accumulated senescent cells in bone/bone marrow of old mice (vs. young mice) and AD mice (vs. wild-type mice). These senescent cells are primarily bone/bone marrow mononuclear pre-osteoclasts (Pre-OCs), which acquire a unique SASP, with PDGF-BB as the highest expressed factor. Importantly, serum PDGF-BB levels were markedly elevated in old animals (vs. young animals) and AD mice (vs. control mice), and ablation of the Pre-OCs reduced serum PDGF-BB concentration. Our results suggest that Pre-OCs in bone/bone marrow is a main source of elevated circulating PDGF-BB during aging and AD progression. While PDGF-BB maintains the homeostasis of the cerebral vasculature under physiological conditions, abnormally high concentration of PDGF-BB may lead to brain vascular impairment. Indeed, we found that ablation of Pre-OCs attenuated age-associated cerebral vascular impair. Our central hypothesis is that the senescent Pre-OCs in bone/bone marrow secrete excessive PDGF- BB into blood circulation, leading to cerebral vascular impairment to accelerate brain aging and AD progression. In Aim 1, we will determine the contribution of SnBCs to normal brain aging and AD progression using bone marrow transplantation approach and genetic mice to induce Pre-OCs ablation. We will examine the changes of brain pathologies and cognitive deficits during aging and AD progression. In Aim 2, we will determine the role of PDGF-BB secreted by SnBCs in brain aging and AD progression by systemically administering a PDGF-BB neutralizing antibody (Ab) and employing genetic mice to knock-out or knock-in PDGF-BB in Pre-OCs. We will examine the changes of brain pathologies and cognitive deficits during aging and AD progression. Positive findings in this study will provide new understanding on relationship between brain and bone in the development of neurodegenerative disease and present an unconventional but promising path for early treatment of AD.